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Candida albicans, normally found as a commensal in the gut, is a major human fungal pathogen responsible for both mucosal and systemic infections in a wide variety of immunocompromised individuals, including cancer patients and organ transplant recipients. The gastrointestinal tract represents a major portal of entry for the establishment of disseminated candidiasis in many of these individuals. Here we report the development of a diet-based mouse model for disseminated candidiasis acquired via the gastrointestinal tract. Using this model, as well as an appropriate immunosuppression regimen, we demonstrate that dissemination of C. albicans from the gastrointestinal tract can result in mortality within 30 days postinfection. We also show a significant increase in fungal burden in systemic organs, but not gastrointestinal tract organs, upon immunosuppression. Importantly, we demonstrate that the administration of two widely used antifungals, fluconazole and caspofungin, either pre- or postimmunosuppression, significantly reduces fungal burdens. This model should prove to be of significant value for testing the ability of both established and experimental therapeutics to inhibit C. albicans dissemination from the gastrointestinal tract in an immunocompromised host as well as the subsequent mortality that can result from disseminated candidiasis., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Objectives: Candida species are major causes of invasive mycoses in immunocompetent and immunocompromised hosts. Treatment options are limited in the setting of antifungal resistance and increased rates of echinocandin-resistant Candida glabrata have been reported. The novel arylamidine T-2307 demonstrates potent in vitro antifungal activity against Candida species. Our objective was to evaluate the in vitro and in vivo activity of T-2307 against resistant C. glabrata., Methods: In vitro activity was determined against 42 clinical C. glabrata isolates, including 17 echinocandin-resistant strains. Neutropenic ICR mice were inoculated intravenously with an echinocandin-resistant C. glabrata isolate (T-2307; caspofungin MICs ≤0.008 and 0.5 mg/L, respectively). Therapy with vehicle control, T-2307 (0.75, 1.5, 3 or 6 mg/kg subcutaneously once daily) or caspofungin (1 or 10 mg/kg intraperitoneally once daily) began 1 day post-challenge. Kidneys were collected on day 8 and fungal burden was assessed by counting cfu., Results: T-2307 demonstrated potent in vitro activity against C. glabrata (geometric mean MIC 0.0135 mg/L), which was maintained against echinocandin-resistant isolates (geometric mean MIC 0.0083 mg/L). T-2307 also demonstrated in vivo efficacy in mice infected with echinocandin-resistant C. glabrata. Significant reductions in fungal burden were observed at each dosage level of T-2307 compared with control. Reductions in fungal burden were also observed with high-dose caspofungin., Conclusions: T-2307 demonstrated potent in vitro activity against C. glabrata, including echinocandin-resistant isolates, which translated into in vivo efficacy against invasive candidiasis caused by an echinocandin-resistant C. glabrata strain. These results demonstrate the potential for T-2307 as therapy against echinocandin-resistant Candida., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: Aminocandin is an investigational echinocandin with excellent activity against Candida species, including Candida albicans and Candida tropicalis. However, few data are available for this agent versus Candida glabrata. We compared the in vitro potency and in vivo efficacy of aminocandin and caspofungin against clinical isolates of C. glabrata including those with reduced caspofungin susceptibility (MIC > 2 mg/L)., Methods: In vitro activity was assessed using microdilution broth susceptibility testing. Three isolates, one with a low and two with elevated caspofungin MICs, were chosen and mice were infected with C. glabrata followed by a single dose of aminocandin or caspofungin (0.5-100 mg/kg), or daily doses of caspofungin (0.07-14.3 mg/kg) begun 1 day after inoculation. Reduction in fungal burden, assessed in kidney tissue on day 8 post-inoculation, was the marker of antifungal response., Results: Aminocandin was more potent than caspofungin against each isolate with reduced caspofungin susceptibility. Mice infected with the caspofungin-susceptible isolate had significant decreases in tissue burden with low doses of either drug. Higher single doses of aminocandin (> or = 10 mg/kg) were required to reduce fungal burden against the two isolates with elevated caspofungin MICs. Single dose administration of caspofungin was ineffective against one of these isolates, and higher daily doses were required to reduce fungal burden., Conclusions: These studies suggest that aminocandin has the potential for extended interval dosing in the treatment of C. glabrata infections caused by susceptible isolates. However, higher doses may be required against isolates with reduced caspofungin susceptibility.

Objective: Amphotericin B failure is frequently seen in patients with candidaemia caused by Candida rugosa. We evaluated amphotericin B, fluconazole, posaconazole and voriconazole as alternative treatments against infection in mice with two isolates of C. rugosa., Methods: Neutropenic mice were inoculated intravenously with C. rugosa. Amphotericin B, fluconazole, posaconazole and voriconazole were administered for 7 days after infection. Efficacy of the antifungal treatment was assessed by survival and tissue burden of C. rugosa., Results: All of the four drugs significantly prolonged survival over controls. With both isolates, kidney counts were reduced significantly below controls for amphotericin B, fluconazole and posaconazole. However, voriconazole was less effective than the other antifungals., Conclusion: Despite poor clinical response to amphotericin B, in vivo data indicate that amphotericin B increases organ clearance and survival over untreated controls. However, although voriconazole improved survival over controls, increased tissue clearance was not seen. This discrepancy may be caused by rapid clearance of voriconazole in mice. These studies suggest fluconazole, posaconazole or voriconazole may be useful alternatives to amphotericin B in therapy of C. rugosa infection.

A patient with azole-refractory thrush-esophagitis responded initially to caspofungin, but the treatment eventually failed. In a murine model, caspofungin was effective against two early isolates for which the MICs of caspofungin were low, but it was less effective against a late isolate for which the MIC of caspofungin was greater. We concluded that there is a correlation between in vivo failure and rising in vitro caspofungin MICs.

Caspofungin is a potent antifungal inhibiting glucan synthesis in Candida species. However, caspofungin is not 100% curative in candidiasis. Therefore, we evaluated combinations of fluconazole with caspofungin for murine candidemia. We could not show any benefit of combined therapy over individual antifungal drugs.

Background: Echinocandins are recommended as first-line therapy against Candida glabrata infections, although increased resistance to this class has been reported worldwide and they are currently only available for parenteral administration. SCY-078 is an investigational glucan synthase inhibitor that is orally available.Objectives: To evaluate the in vivo efficacy of SCY-078 in an experimental model of invasive candidiasis due to WT and echinocandin-resistant C. glabrata isolates.Methods: Neutropenic ICR mice were inoculated intravenously with a WT isolate (SCY-078 and caspofungin MICs 0.25 and 0.125 mg/L, respectively) or an echinocandin-resistant isolate (SCY-078 and caspofungin MICs 1 and 0.5 mg/L, respectively). Treatment with placebo, SCY-078 (8, 30 or 40 mg/kg orally every 12 h) or caspofungin (1 mg/kg by intraperitoneal injection once daily) began 24 h later. Kidney fungal burden was measured on day 8 post-inoculation.Results: Significant reductions in kidney fungal burden were observed with 30 mg/kg SCY-078 against both isolates and with the 40 mg/kg dose against the echinocandin-resistant isolate. These results were supported by SCY-078 plasma concentration data at the higher doses, where levels above the MICs for both isolates were observed 12 h after the last oral dose. Reductions in fungal burden were also observed with caspofungin against the WT isolate, but not against the resistant isolate.Conclusions: SCY-078 demonstrated in vivo efficacy against infections caused by both WT and echinocandin-resistant C. glabrata isolates in this experimental model. This orally available glucan synthase inhibitor has potential as a therapy against echinocandin-resistant C. glabrata infections. [ABSTRACT FROM AUTHOR]

Background Candida auris is an emerging pathogen associated with antifungal resistance and high mortality. The novel antifungal manogepix (APX001A) prevents glycosylphosphatidylinositol-anchored protein maturation through inhibition of the inositol acyltransferase Gwt1 enzyme, and has demonstrated in vitro and in vivo activity against numerous pathogenic fungi, including C. auris. We evaluated the efficacy of the prodrug fosmanogepix (APX001) following delayed initiation of therapy in a murine model of C. auris invasive candidiasis. Methods Neutropenic outbred mice (10 per cohort) were inoculated intravenously with C. auris (minimum inhibitory concentrations [MICs]: manogepix 0.03 mg/mL, fluconazole >64 mg/mL, caspofungin 0.25 mg/mL).Treatment with placebo, fosmanogepix (104 or 130 mg/kg by intraperitoneal injection [IP] three times daily, or 260 mg/kg IP twice daily), fluconazole (20 mg/kg/day orally), or caspofungin (10 mg/kg/day IP) began 1 day later and continued for 7 days. Mice were followed post therapy until day 21 to assess survival. Kidneys and brains were collected on day 8, on the days that mice succumbed to infection, or on day 21. Fungal burden was assessed by colony-forming units (CFU). Results Survival was significantly improved at each dose level of fosmanogepix (median >21 days; 90–100%) and high dose caspofungin (>21 days; 90%) compared with placebo (5 days; 10%; P < 0.0001). On day 8 post-inoculation, kidney and brain fungal burdens were significantly reduced in mice treated with fosmanogepix 260 mg/kg BID compared with placebo and in kidneys of mice treated with caspofungin (Table 1). In the survival arm, fungal burden in kidneys and brains was significantly lower at each dose level of fosmanogepix and with high dose caspofungin compared with placebo. In contrast, no improvements in survival or reductions in fungal burden were observed with fluconazole. Conclusion Fosmanogepix demonstrated potent in vivo activity against invasive candidiasis caused by C. auris even with delayed initiation of treatment. Improvements in both survival and reductions in fungal burden within the kidneys and brains were observed. These data demonstrate the potential utility of fosmanogepix against C. auris infections. Disclosures All Authors: No reported Disclosures. [ABSTRACT FROM AUTHOR]